The underlying primary hypothesis, that intervertebral disc degeneration contributes to low back pain, and a second hypothesis, that the process of degeneration can be prevented, retarded or repaired, of this renewal Program Project Grant remain. The four projects of the ongoing Program Project Grant form the basis for this competitive renewal application and have achieved an improved understanding of the biomechanical and metabolic factors involved in intervertebral disc degeneration. Project 1 developed a new precise and reproducible non-invasive 3-D analysis method of measuring segmental motion of the lumbar spine. Project 2 developed and validated a finite element model, which includes fluid flow and the poro-elastic behavior of the intervertebral disc. Project 3 identified biochemical changes in collagens, proteoglycans, and matrixdegrading enzymes in the intervertebral disc that are associated with aging and/or tissue degeneration. Project 4 developed an annular puncture rabbit model of acute or sub-acute intervertebral disc degeneration and showed that the injection of growth factor up-regulates matrix synthesis with restoration of disc height. In this renewal proposal, we have designed experiments that are mechanistic, hypothesis-driven and potentially translational to further advance our understanding of the biomechanical and biological factors associated with intervertebral disc degeneration. Project 1 will measure kinematic hypermobility in torsion and flexionextension in vivo and correlate those data with low back pain symptoms. Factors of prognostic importance to the progression of disc and facet joint degeneration and symptoms will be identified. Project 2 will focus on developing a finite element model that more closely corresponds to a degenerative disc and will study its response to repetitive loading. Project 3 will determine the mechanism of action and interplay between growth factors, cytokines and different regulatory molecules in disc tissue homeostasis and their potential use in promoting disc tissue repair. Project 4 will determine if disc degeneration can be delayed or reversed by manipulating the balance between anabolic and catabolic pathways and if compromised nutrient transport through the endplate limits cell-mediated disc repair induced by the application of a growth factor. This Program Project will result in major progress that will directly translate into relief for so many individuals suffering from low back pain that is associated with intervertebral disc and facet joint degeneration.